Cocaine dependence is a chronic condition because of the high incidence of relapse that occurs even after prolonged periods of abstinence. Thus, successful treatment must include relapse prevention. The objective of this grant is to elucidate the neural mechanisms underlying incentive motivational effects produced by sampling cocaine or by exposure to cocaine-associated cues (e.g., paraphernalia, cocaine- taking environment, etc), both of which are thought to play a major role in cocaine craving and relapse. Incentive motivational effects of cocaine and cocaine cues involve dopamine (DA), serotonin (5-HT), and glutamate systems. Furthermore, there is mounting evidence that suggests cocaine and cocaine cues activate different, but overlapping neural circuits and much attention has been given to understanding the role of DA and glutamate within these circuits. In contrast, little research has examined the role of 5-HT in these circuits. Recent research suggests that stimulation of 5-HT2C receptors (Rs) inhibits mesolimbic DA neurons and decreases the incentive motivational effects of both cocaine and cues, whereas stimulation of 5-HT2ARs may facilitate incentive motivational effects of these stimuli. The proposed research will examine specific hypotheses regarding the anatomical locus of these effects. Specifically, we hypothesize that increased stimulation of 5-HT2CRs in the amygdala inhibits incentive motivational effects of cocaine cues, whereas stimulation of these receptors in the ventral tegmental area inhibits incentive motivational effects of both cues and cocaine itself. Furthermore, we hypothesize that stimulation of 5-HT2CRs in the medial prefrontal cortex inhibits the incentive motivational effects of these stimuli, whereas stimulation of 5-HT2ARs in this region facilitates the effects. The hypotheses will be tested by examining the effects of localized infusions of 5-HT drugs on reinstatement of extinguished cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) following cocaine priming injections or exposure to cocaine cues. Contingent upon support for predicted effects, subsequent experiments will examine the anatomical and pharmacological specificity of the effects. This research will help to elucidate the role of 5-HT in the neural circuits underlying incentive motivational effects of cocaine and cocaine cues. Understanding these circuits will likely have important implications for developing treatments for cocaine dependence.